The present invention relates to methods and compositions for the synthesis of multimerizing agents.
AP20187 is a small organic compound [CAS Registry No. 195514-80-8, molecular weight 1482.75] that induces controlled biological processes within cells having appropriate genetic alterations. AP20187 and related compounds provide a means for regulating genetically modified cells on the principle that intracellular signaling mechanisms can be regulated by specific protein-protein interactions. By selecting protein interactions that produce a desired cellular response and engineering those proteins to interact only in the presence of a small-molecule multimerizing agent, such as AP20187, it is possible to bring complex biological processes under direct control. For example, AP20187 can be used to regulate the production of therapeutic proteins and to control signal transduction in genetically altered cells to control cell death, proliferation, immune function, etc. The broad utility of AP20187 and other multimerizers has led to a significant body of scientific publications involving a range of biological contexts.
AP20187 includes multiple stereocenters. The configuration at each of the stereocenters has been found to be important to the biological activity of the compound. That structural complexity and chirality is also an important consideration in the production of the compounds. While methods and materials for the synthesis of AP20187, and related compounds, are disclosed in U.S. Pat. No. 6,150,527, new methods and intermediates which lend themselves to greater product purity and to greater overall efficiency, convenience, economics and/or scalability are particularly desirable.